The pancreas is an organ which has endocrine and exocrine cells and plays an important role in both internal and external secretions. It is known that endocrine cells serve to produce and secret pancreatic hormones, and α cells, β cells, δ cells and PP cells secrete glucagon, insulin, somatostatin and pancreatic polypeptides, respectively. In particular, insulin has an activity for decreasing a blood sugar level, and plays an important role in maintaining a blood sugar level at the normal concentration.
In recent years, a polypeptide known as human TM4SF20 or a fragment thereof has been reported to have an activity for promoting increase in pancreatic β cells (see Patent Document 1). The base sequence of a DNA that encodes human TM4SF20 is set forth in SEQ ID NO: 2, and the amino acid sequence of human TM4SF20 is set forth in SEQ ID NO: 3. This polypeptide or a fragment thereof can potentially be used for treating diseases associated with decrease or death of pancreatic β cells, in particular, for treating Type I diabetes mellitus.
However, the polypeptide (human TM4SF20) described in Patent Document 1 comprises 229 amino acid residues, and thus a peptide with a shorter the length of amino acid residues is desired for practical use. Although Patent Document 1 also describes 3 fragments (Peptides A, B, C) comprising 19 amino acid residues as a peptide with a shorter length of amino acid residues, the activity for promoting increase in pancreatic β cells was not as high as expected. The amino acid sequences of Peptides A, B, C are set forth in SEQ ID NOs: 4 to 6, respectively. Note that the amino acid sequences of Peptides A, B, C correspond to the amino acid sequences from Position 98 to 116, from Position 78 to 96 and from Position 161 to 179 of human TM4SF20, respectively.
Further, in recent years, pluripotent stem cells such as induced pluripotent stem cells (hereinafter also referred to as “iPS cells”) and embryonic stem cells (hereinafter also referred to as “ES cells”), or many methods for inducing differentiation of pancreas tissue stem/precursor cells into pancreatic hormone-producing cells have been reported (see Nonpatent Documents 1 to 4, Patent Documents 2 to 7 and the like). If pancreatic hormone-producing cells can be efficiently obtained by these differentiation-inducing methods, a method of treating Type I diabetes mellitus is expected to become a substitute for pancreatic islet transplantation. Furthermore, the problem of rejection can also be solved if pancreatic hormone-producing cells can be obtained from pluripotent stem cells or pancreas tissue stem/precursor cells derived from a patient himself/herself.
However, none of the differentiation-inducing methods reported to date has a sufficient differentiation-inducing efficiency into pancreatic hormone-producing cells. Accordingly, a differentiation-inducing method capable of high efficiency inducing differentiation into pancreatic hormone-producing cells has been desired. In particular, a differentiation-inducing method without a gene transfer is preferred in view of safety.    Patent Document 1: PCT International Publication No. WO2009/013,794    Patent Document 2: PCT International Publication No. WO2007/103,282    Patent Document 3: PCT International Publication No. WO2005/063,971    Patent Document 4: PCT International Publication No. WO2009/048,675    Patent Document 5: PCT International Publication No. WO2007/051,038    Patent Document 6: PCT International Publication No. WO2006/108,361    Patent Document 7: PCT International Publication No. WO2008/066,199    Non-Patent Document 1: D'Amour, K. A. et al., Nature Biotechnology, 24, pp. 1392-1401(2006)    Non-Patent Document 2: Wei Jiang et al., Cell Research, 17, pp. 333-344(2007)    Non-Patent Document 3: Miyazaki, S. et al., Diabetes, 53, pp. 1030-1037(2004)    Non-Patent Document 4: Yuya Kunisada et al., Stem Cell Research, 8, pp. 274-284(2012)